Tissue repair is a finely organized process that progresses via a series of phases, including hemostasis, inflammation, proliferation, and remodeling, which are coordinated by immune–stromal interactions. Aging profoundly dysregulates these processes through mechanisms such as immunosenescence and inflammaging, cellular senescence, chronic inflammation, and extracellular matrix alterations, ultimately contributing to typical age-related progression. This review discusses the immune mechanisms that govern physiological tissue healing, as well as the age-related perturbations that lead to ulcerative and fibrotic diseases. It also highlights the potential application of extracellular vesicles (EVs), both mammalian and plant-derived, as a stable and low-immunogenicity mediator to modulate and re-establish repair homeostasis. Translational hurdles such as EV standardization, dosing, safety assessment, and manufacturing are critically discussed to promote their use in geroscience, regenerative medicine, and dermatology.

Centenarians, semi-supercentenarians and supercentenarians (i.e. oldest centenarians) display complex and heterogeneous immune remodelling. In this setting, immune at-trition, memory, cytotoxic defence, inflammatory regulation and tissue surveillance remain sufficiently balanced to support survival with relatively preserved health. This review examines these processes within an integrated framework encompassing sex and gender differences, genetic background, the exposome and immunobiography. We consider how haematopoietic stem cell ageing, age-related myeloid bias, thymic invo-lution, immune ageing and inflammaging contribute to immune-system remodelling across the life course. We then review evidence on immunity in centenarians and in semi- and supercentenarians, including NK cell expansion, T and B cell remodelling and the persistence of long-term immunological memory, as characterised by conventional flow cytometry and, more recently, single-cell transcriptomic analyses. Available data suggest that exceptional longevity does not reflect the maintenance of a youthful immune system, but rather the capacity to accommodate and compensate for age-related immune re-modelling through preserved cytotoxic surveillance, controlled inflammation, main-tained immune memory and favourable lifelong adaptation to antigenic exposures. Understanding these mechanisms may help identify immune trajectories associated with healthspan, delayed morbidity and resistance to age-related diseases.

Centenarians, semi-supercentenarians and supercentenarians (i.e., oldest centenarians) display complex and heterogeneous immune remodelling. In this setting, immune attrition, memory, cytotoxic defence, inflammatory regulation and tissue surveillance remain sufficiently balanced to support survival with relatively preserved health. This review examines these processes within an integrated framework encompassing sex and gender differences, genetic background, the exposome and immunobiography. We consider how haematopoietic stem cell ageing, age-related myeloid bias, thymic involution, immune ageing and inflammaging contribute to immune-system remodelling across the life course. Findings from conventional phenotyping and single-cell transcriptomic studies in centenarians, semi-supercentenarians and supercentenarians indicate selective immune remodelling rather than preservation of a youthful immune system. These changes include NK-cell expansion, differentiated B-cell states, enrichment of effector-memory CD8⁺ T cells, marked expansion of clonally selected cytotoxic CD4⁺ T cells and increased GZMK⁺GZMB⁻ CD8⁺ T cell populations. Exceptional longevity also appears to depend on limiting the detrimental consequences of chronic inflammation through delayed or better-controlled inflammaging, restrained NLRP3 inflammasome activation and preserved capacity to buffer oxidative stress. Thus, extreme survival appears to reflect successful accommodation of age-related immune change through sustained cytotoxic surveillance, immune memory, inflammatory control and favourable lifelong adaptation to antigenic exposures.